Prevention of severe RSV infection by a helminth-induced serum factor that elicits antiviral monocytes?

在全世界的婴儿和幼儿中，呼吸道合胞病毒（RSV）是一种称为细支气管炎的胸部感染的最常见原因，并导致严重的肺部炎症。在英国，2-3%的婴儿必须因RSV细支气管炎住院，其中一些婴儿发展为非常严重的，有时危及生命的疾病。当感染后存在非常高数量的病毒颗粒时，尤其如此。由于治疗成本和更广泛的社会成本（例如父母/护理人员的工作日损失），RSV造成了重大的经济负担。尽管如此，没有具体的治疗或有效的，广泛可用的预防性干预措施存在，迫切需要新的方法。帕利珠单抗是一种针对RSV的预防性抗体，可以预防约50%的住院，但由于成本高，其使用仅限于富裕国家的一小群高危婴儿。我们以前曾报道过，在RSV感染的小鼠模型中，肠道寄生虫感染可以减少肺部病毒颗粒的数量和疾病的严重程度。最近，我们发现在该模型中对严重RSV感染的保护与骨髓中称为单核细胞的免疫细胞的产生增加及其在肺中的积累有关。单核细胞被认为在对RSV的免疫反应中很重要，但它们如何发挥抗病毒作用尚不完全清楚。重要的是，寄生虫感染的所有上述影响都可以用受感染小鼠的无细胞血清重现，除非它已经加热。这表明血清中的蛋白质，如免疫系统信使分子，作为可溶性RSV保护因子的核心作用。如果我们能够确定这个因素，并找出它的作用，我们将来可能能够开发一种新的方法来保护幼儿免受严重RSV疾病的侵害。在这里，我们将首先使用我们的小鼠模型来研究在寄生虫感染期间发生哪些单核细胞亚群以及哪些单核细胞基因被“打开”，以确定单核细胞限制RSV感染的机制。然后，我们将使用两种方法从血清中鉴定RSV保护因子;一种方法是测量、阻断和替换血清中已知的候选免疫介质，另一种方法是测试不同大小的血清蛋白组的抗RSV作用，然后测量有效组内的蛋白质并鉴定候选因子。然后将单独测试它们的抗病毒效果，并确定RSV保护因子。最后，为了将我们的发现从小鼠模型转化为人类，我们将使用来自乌干达儿童的现有血液样本，无论是否有肠道寄生蠕虫。我们将评估基因的激活，看看那些寄生虫感染者的血液中是否也有更多的单核细胞和更活跃的抗病毒基因，我们将测量新发现的RSV保护因子的浓度，看看它是否在寄生虫感染的儿童中升高。这些研究将使我们发现哪种寄生虫诱导的因子负责保护RSV感染以及单核细胞如何有助于这种保护。他们还将告诉我们RSV保护因子和/或单核细胞是否将成为开发严重RSV细支气管炎预防性治疗的有希望的新靶点。

In babies and toddlers worldwide, respiratory syncytial virus (RSV) is the most common cause of a type of chest infection called bronchiolitis and causes severe lung inflammation. 2-3% of all babies in the UK have to be admitted to hospital with RSV bronchiolitis and some of them develop very severe and sometimes life-threatening disease. This happens particularly when very high numbers of virus particles are present after infection. Due to treatment costs and costs for the wider society (e.g. days lost at work for parents/ carers) RSV is responsible for a major financial burden. Despite all of this, no specific treatment or effective, widely available preventative interventions exist and novel approaches are urgently required. Palivizumab, a prophylactic antibody against RSV, can prevent hospital admissions by about 50% but due to high cost its use is limited to small groups of high-risk infants in affluent countries. We have previously reported that infection with a gut parasite worm can reduce the number of viral particles in the lungs and disease severity in a mouse model of RSV infection. More recently, we have found that protection from severe RSV infection in this model is associated with increased production of immune cells called monocytes in the bone marrow and their accumulation in the lung. Monocytes are thought to be important in the immune response to RSV, but how they exert their antiviral effect is not fully understood. Importantly, all the above effects of parasite infection can be recapitulated with cell-free blood serum from infected mice, unless it has been heated. This suggests a central role for a protein in the serum, such as an immune system messenger molecule, as the soluble RSV-protective factor. If we can identify this factor, and work out what it is doing, we may in the future be able to develop a novel approach to protection from severe RSV disease in young children. Here, we will initially use our mouse model to study which subgroups of monocytes occur and which monocyte genes are 'switched on' during parasite infection, in order to define the mechanisms by which monocytes limit RSV infection. We will then use two approaches to identify the RSV-protective factor from blood serum; one where we measure, block and replace known candidate immune mediators in the serum, and another where we test groups of serum proteins of different sizes for their anti-RSV effect, followed by measurement of the proteins within the effective group and identification of candidate factors. These will then be tested individually for their antiviral effect and the RSV-protective factor will be identified. Finally, to translate our findings from the mouse model to humans, we will use existing blood samples from Ugandan children with and without gut parasite worms. We will assess the activation of genes to see if those with parasite infection also have more monocytes and more active anti-viral genes in their blood and we will measure the concentration of the newly identified RSV-protective factor to see if it is elevated in parasite-infected children. These studies will let us find out which parasite-induced factor is responsible for the protection from RSV infection and how monocytes contribute to this protection. They will also tell us if the RSV-protective factor and/or monocytes will be promising new targets to develop preventive treatment for severe RSV bronchiolitis.